Preparation of substituted piperazinium salts



United States Patent 3,373,162 PREPARATRQN 0F SUBSTITUTED PiPERAZiNIUh i SALTS Clarence R. Dick, Lake Jackson, Tex assignor to The Dow Chemical Company, Midland, Mich, a corporation of Delaware No Drawing. Filed Nov. 16, 1W5, Ser. No. 598,138 6 iii-aims. (Cl. 266-258) ABSTRACT OF THE DESCLOSURE Substituted piperazinium halides are made by the reaction of an N-substituted aziridine with an alkylating agent in the presence of a source of halogen ion.

This invention relates to a process for preparing 1,1,4- trisubstituted piperazinium salts.

The preparation of piperazine by dimerization of aziridine (ethylenimine) has long been known to the art. Quite logically, the preparation of substituted piperazininum salts has proceeded from substituted piperazines. But the latter reactions are less than satisfactory for commercial practice because they are Inulti-step, give only moderate yields, and produce a variety of by-products.

It has now been discovered that 1,1,4-trisubstituted piperaziniurn halides can be obtained by a single-step procass in high yields essentially free of undesired lay-products. These piperazinium salts are useful as curing agents for epoxy resins. They are also useful as intermediates and for their activities in modified degrees in the medical and veterinary appliactions for the piperazines.

This novel process in its broadest aspect comprises the reaction of an N-substituted aziridine with an alkylating agent in the presence of or including a halogen in accord with the following reaction scheme:

R above is a hydrocarbon radical conferring on the N- substituted aziridine a K value greater than l0 [AA] is an alkylating agent supplying R and X, R is a monoor divalent hydrocarbon radical having its valence or valences on an aliphatic carbon atom and containing 1 through carbon atoms, and X is chlorine, bromine or iodine.

. The hydrocarbon substituent on the aziridine nitrogen can be defined in terms of the K value of the thus substituted aziridine in view of the discovery that aziridines having relatively low K values were substantially inoperative in this process. For example, cyanoethylaziridine (K =2.8 1O will produce only polymerized products. Other compounds, such as 2-acet0xyethyl aziridine (K =3.5 X 10- are operative but only in low yields. On the other hand, illustrative of the reactions of this invention, N-ethyl arizidine (K =8.1 l0 delivers nearly quantitative yields of piperazine products.

The N-substituent is thus constituted as desired within the foregoing limitation to give the appropriate substituent at R on the piperazine nucleus. Advantageonsly, R is a hydrocarbon group containing 1 to about 10 carbon atoms, such as cycloalkyl (e.g., cyclopentyl, cyclohexyl), alkenyl (e.g., allyl, vinyl), alkynyl (e.g., ethynyl propynyl), aralkyl (e.g., benzyl, phenylethyl), aryl (e.g., phenyl) and the like. Preferred, however, are the alkyl groups containing 1 to about 10 carbon atoms (e.g., methyl, ethyl, propyl, isopropyl, butyl, decyl, secbutyl, tbutyl and the like) A principal difficulty in conducting the conversion of N-substituted aziridines to substituted piperazinium salts is averting polymerization to a polyaziridine as the dominant reaction. Studies in conjunction with this invention have shown the necessity for the halide ion in piperazine formation, and this is conveniently supplied in the form of the anion constituent of the selected hydrocarbon halide alkylating agent or by a metal halide accompanying a non-halide alkylating agent. In present context, therefore, the term alkylating agent includes conventional non-halide alkylating materials employed in the presence of a halide as Well as conventional alkylating materials which are themselves halides. For example, such alkylating agents include the hydrocarbon halides of the type RX, in which R is the desired hydrocarbon radical to be introduced as the R substituent of the piperazinium salt. R can be alkyl, alkenyl or aralkyl as defined above. It is to be noted that the benzene nucleus of the aralkyl groups can contain halide, nitro, ether and other non-reactive substituents where such is desired in the final piperazinium product. Such alkylating agents also include the arylsulfonates (e.g., benzenesulfonate) and substituted arylsulfonates (e.g., p-toluenesulfonate, p-chlorobenzenesulfonate, p-nitrobenzenesulfonate, p-methoxybenzenesulfonate and the like), in the essential presence of a metal halide such as sodium or potassium iodide.

The reaction will proceed at temperatures above about 10 C., e.g., to the boiling temperature of the reaction mixture at atmospheric pressure, although a range of about 20 to about 60 C. is preferred. Such reaction should generally be permitted to continue until the halide has been substantially consumed in orderto maximize yields. lrogress of the reaction is conveniently checked at intervals by gas-liquid chromatography. A reaction time of ten minutes to 18 hours is generally employed.

Presence of the N-substituted aziridine in moderate excess favors hi h yields. While stoichiometric amounts of the N-substituted aziridine and halide (in, two moles and one mole, respectively) are operative, a molar ratio of about 6:1 to 12:1 of N-substituted aziridine to halide produces a more satisfactory reaction. Excess N-substituted aziridine beyond a molar ratio of about 12:1 is generally to be avoided because of product loss during recovery and, on occasions, the formation of polymeric byproducts. A ratio of about 10:1 preferred.

In general, non-aqueous solvents for the reactants are preferred. The usual organic solvents, such as the lower alcohols (e.g., ethanol, propanol) and ketones (e.g., acetone, rnethylethyl ke-tone), are normally acceptable. Water alone is to be avoided as favoring polymerization, although the presence of small amounts usually can be tolerated. No special sequence of mixing need be observed, and recovery of the reaction product is by conventional methods.

An outstanding feature of this reaction is the high yields of product obtained. Based on starting halide, yields generally are above 50 percent and in most cases exceed percent or are virtually quantitative, as will be noted below.

The following examples illustrate the process of this invention but are not intended to limit its scope.

Example 1.-1,1,4-triethylpiperazinium bromide A reaction vessel equipped with means for stirring and temperature control was charged with 25.6 gm. of N-et-hyl aziridine and 36 m1. of dry acetone. To this mixture was added 2.25 gm. of ethyl bromide. The temperature was maintained at 25 C. for 8 hours. As the reaction proceeded the solution became cloudy, and a precipitate formed and settled to the bottom of the vessel. This precipitate was removed by filtration, washed with die-thyl ether and dried to give 7.48 gm. (99+ percent of theoretical) of 1,1,4-triethylpiperazinium bromide, M.P. 202- 205 C. Analysis:

nitrogen found, 11.21 percent;

R being a monoor divalent hydrocarbon radical having its valance or valences on an aliphatic carbon atom and containing 1 through 20 carbon atoms, and X is chlorine,

bromine or iodine, to give a 1,1,4-trisubstituted piperazinium salt of the formula nitrogen calculated, 11.15 percent.

CHr-CH R 69 9 Example 2.1,4-diethyl-1-methylpzperazzmum iodide R X CHrCHz R To 100 ml. of dry acetone was added 0.36 mole (25.6 wherein R, R and X are as above defined. gm.) of 1-ethylaziridine, 0.036 mole (5.5 gm.) of sodium 2. The process of claim 1 wherein the reaction con- O iodide and 0.036 mole (6.84 gm.) of methyl p-toluenedlltled at temperature above about sulfonate. The temperature of the mixture was mainf j P clalm 1 Whereln the mole ratio of tained at 30-35 C. by cooling the exothermic reaction 15 Z f f 5 k 1 d and was then held at room temperature for 12 hours. g f' 0 1 eremhR fg 52% Acetone (400 ml.) was added to the reaction mixture, i f g 1 Sal a y groups" avmg mug i iv ite r itat of which s then filtered to g e a Wh p eclp e 5. The process of claim 4 wherem the reaction 1s consodiu-m p-toluenesulfonate. The acetone extract was ducted with a molar excess of about to about 121 evaporated to give a pale yellow gum which wa P N-substituted aziridine over alkyl halide. verted to a solid precipitate by repeated washings with A pl-oqsss for preparing a 1,1,4-trisubstituted piperethyl ether- Anallms f F P bfl L azinium halide which comprises: (1) reacting (a) an N- drethyl-Lmethylprperazmmm iodide in 98 percent yield Substitutedazirldine f The fo l and 96 percent purity. CH2

Following specifically the procedure of Example 1, other reactions were conducted and products obtained as follows: CH2

CH2 Clair-C32 /R [AA]RX RN\ R-N X- (A) (B) CH2 OH2CH2 R RX [R] Molar Reaction Percent M.P., Examples (A) (B) (gating) 'Ileglp, Product Yield 1 C.

RX [R-] Molar Reaction Percent M.P., Examples (A) (B) ($211213 'Tgrgp Product Yield 1 C.

10 1 1Aqgethyl-l-allylpiperazinium bromide. .8- .5; 10:1 -0 o 1 2-1" Example 5---. 20:1 1,-but-Z-enebis(Lt-diethylplperazinium chloride) 88 197-200 Example 6. 10:1 40 1,4-d ethyl-l-allylp peraznnum chlor de 96 140-143 Example 10:1 25 1,l-d ethyl-l-allylplperazunum brom1de 80 Example 8 10:1 25 1,4-d ethyl-l-butylplperanimum bromide 96 Example 9---- 10: 1 25 1,4-d1ethyl-1-al1ylp1perazln um chloride... 91 Example 10--. a,a-dibromoxylene do. 20:]. 25 a,a-xyleneb1s(1,4-d1ethylp1perazrmum br 2 99 Example 11--. Methyl iodide do 18:} 1,tg et l yhl methylpiperagn um IOdldtL- 3; Exam 1e 12 Eth liodide -do rle yplperazimurn 10 l e Examgle 13 n-Dgdecyl bromide 10:1 25 1,4-diethyl-l-dodecylpiperarinium bromide. 92 Example 14--. Allyl bromide 10:} lA-dbutyH-allylplperazmmm bromide 134F135 5 Exam le15 do 10: 0 Examgle 16--- Al1y1chloride 10:1 25 1,4-dibutyl-1-allylpiperazinium chloride 94 151-154 Example 17 Allyl bromide. 10:1 40 1,4-(2-phenylethyl)-1-a.llylp}perazin1um bromide 93 161-164 Example 18-.- Allyl chloride "go"- 1( 1,4-(Z-phenylethyl)-1-a11y1p1peraz1.mum chloride 33 {gar-1% Exam le19 Allyl chloride o 1 0 p +sodiu1n iodide Example 20--- Ethyl bromide 10:1 25 1,4-d1methy1-1-ethylplperazmmm bromide 99 155-157 Example o 10:1 25 1,4decyl-l-ethylp1perazimumbrom1de 90 193-196 Example 22 Chloroaeetoneuu 10:1 25 1,4 diethyl-l-methylacetopiperazmium ehlori 75 177-179 Example 23--. 1,6-dibromohexane do 20:1 25 1,dhexanebistl,4-d1ethy1piperazimum bromide)-.-" 92 236238 1 Recovered product based on moles of halide.

/CH2 RN wherein R is a hydrocarbon radical conferring on said N-substituted aziridine a K value greater than about 10- with (2) an alkylating agent of the formula 9 At 21 percent conversion of a,a-dibromoxylene.

1 to continue until substantially all the halide has been consumed, and (2) separating from the reaction mixture the thus-formed 1,1,4-tri-substituted piperazinium halide of the formula GE -0H2 R-N X OHz-CH: R

wherein R, R and X are as above defined.

No references cited.

HENRY R. JILES, Primary Examiner. 

